Abstract
Preeclampsia is a maternal hypertensive disorder that affects up to 1 out of 12 pregnancies worldwide. It is characterized by proteinuria, endothelial dysfunction, and elevated levels of the soluble form of the vascular endothelial growth factor receptor-1 (VEGFR-1, known as sFlt-1). sFlt-1 effects are mediated in part by decreasing VEGF signaling. The direct effects of sFlt-1 on cellular metabolism and bioenergetics in preeclampsia, have not been established. The goal of this study was to evaluate whether sFlt-1 causes mitochondrial dysfunction leading to disruption of normal functioning in endothelial and placental cells in preeclampsia. Endothelial cells (ECs) and first-trimester trophoblast (HTR-8/SVneo) were treated with serum from preeclamptic women rich in sFlt-1 or with the recombinant protein. sFlt-1, dose-dependently inhibited ECs respiration and acidification rates indicating a metabolic phenotype switch enhancing glycolytic flux. HTR-8/SVneo displayed a strong basal glycolytic metabolism, remaining less sensitive to sFlt-1-induced mitochondrial impairment. Moreover, results obtained in ECs exposed to serum from preeclamptic subjects demonstrated that increased sFlt-1 leads to metabolic perturbations accountable for mitochondrial dysfunction observed in preeclampsia. sFlt-1 exacerbated mitochondrial reactive oxygen species (ROS) formation and mitochondrial membrane potential dissipation in ECs and trophoblasts exposed to serum from preeclamptic women. Forcing oxidative metabolism by culturing cells in galactose media, further sensitized cells to sFlt-1. This approach let us establish that sFlt-1 targets mitochondrial function in ECs. Effects of sFlt-1 on HTR-8/SVneo cells metabolism were amplified in galactose, demonstrating that sFlt-1 only target cells that rely mainly on oxidative metabolism. Together, our results establish the early metabolic perturbations induced by sFlt-1 and the resulting endothelial and mitochondrial dysfunction in preeclampsia.
Highlights
Preeclampsia (PE) is an often-fatal cardiovascular complication related to pregnancy, that affects almost 8% of all pregnancies worldwide
Several reports opened a novel window for understanding the pathogenesis of the disease, by describing the role of circulating anti-angiogenic factors like sFlt-1, in the development and early detection of the disease (Maynard et al, 2003; Levine et al, 2004; Young et al, 2010; Perni et al, 2012; Verlohren et al, 2012). sFlt-1 has been found to provoke endothelial dysfunction (Powe et al, 2011; Sánchez-Aranguren et al, 2014), hypertension (LaMarca et al, 2008) and proteinuria (Maynard and Karumanchi, 2011), demonstrating its culprit role in the onset of PE (Roberts and Rajakumar, 2009)
The present study demonstrates the striking effects of sFlt-1 and serum from PE women in the overall cell energy metabolism, mitochondrial bioenergetics and mitochondrial dysfunction, linked to oxidative stress in Endothelial cells (ECs) and first trimester extravillous trophoblast (EVT) (HTR-8/SVneo cells)
Summary
Preeclampsia (PE) is an often-fatal cardiovascular complication related to pregnancy, that affects almost 8% of all pregnancies worldwide. It is associated with approximately 80,000 maternal and over 500,000 infant deaths annually, impacting the lives of over 4 million women worldwide(Duley, 2009). Uterine blood flow increases to allow adequate perfusion of the placental intervillous space and physiological oxidative stress (Chaiworapongsa et al, 2014). In PE, a prolonged hypoxic placental microenvironment, due to a reduction in placental perfusion and oxygen availability, results in exacerbated oxidative stress (Chaiworapongsa et al, 2014). Hypoxia triggers several cellular responses, including increased placental angiogenesis (Zamudio, 2003), cell survival and metabolic adaptations (Illsley et al, 1984), established in developmental biology as “placental metabolic reprogramming” (Illsley et al, 2010; Jose et al, 2011)
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